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Case report - Introduction The differential diagnosis of paediatric uveitis is extensive. Classification starts by determining infectious versus non-infectious causes, anatomic location and associated intra-ocular and extra-ocular features. A relatively common referral to Paediatric Rheumatology from our Ophthalmology colleagues is of a child with a diagnosis of uveitis. This case highlights the importance and benefits of multidisciplinary team working across our regional network when caring for children with complex and rare conditions. Case report - Case description An 8-year-old-girl was referred by her local ophthalmology team to the paediatric rheumatology clinic with a diagnosis of pars-planitis. She had presented to them with blurred-vision and eye-“floaters”. On review, the girl reported that she had a 4-month-history of headaches and blurred-vision, associated with dizziness. She denied any eye-pain. Corresponding to the onset of her symptoms, she had suffered with Chickenpox. Her mother felt that she had "not been right since then". She noted that she was generally quieter and more fatigued than normal. Over the course of the 4 months, she was noted to have become clumsier and was bumping into things on a regular basis. She reported increasing visual difficulties in her right eye and initially attended for an optician review. The optician was concerned and referred for urgent ophthalmology opinion. She was diagnosed with bilateral pars-planitis, commenced on oral prednisolone and referred for paediatric rheumatology and tertiary ophthalmology assessment. The headaches improved following commencement on steroids. Positive findings on systems review included occasional oral ulcers, 1—2 times-per-month. They started about 1-month prior to the onset of her chickenpox and continued for the following 3—4 months. She denied any history of genital-ulcers or skin-rash. She had new-onset muscle soreness and tiredness after activity. She also described non-specific abdominal pain since having chickenpox, but no associated change in bowel habit. Examination revealed normal skin, hair, nail and joint examination. She had a soft systolic murmur (echocardiogram normal). She had RUQ tenderness on abdominal palpation (abdominal-USS – spleen upper limit of normal. Nil else). Relevant blood and stool samples were sent as part of a uveitis work-up panel. The paediatric ophthalmologist found right-intermediate uveitis with vitreitis and peripheral retinal changes in keeping with a peripheral exudative detachment. Similar changes were seen in the peripheral retina of the left eye. The impression was of bilateral pan-uveitis with retinal involvement. A subsequent oral fluorescein angiogram showed a widespread retinal vasculitis with some occlusive changes in the right-eye, and a tuft of retinal vascular leakage at the 5-o'clock position in the left eye. Case report - Discussion The differential diagnosis for paediatric retinal vasculitis is broad. It includes collagen vascular disorders, Behçet's disease, Eales’ disease, post viral or post vaccination, acquired toxoplasmosis, multiple sclerosis, systemic immunosuppression and Henoch-Schönlein purpura. The ANA, ENAs, dsDNA, ANCA, ACE, Toxoplasma and Lyme serology were all negative for this little girl. Her inflammatory markers were also normal. She was not on any regular medications prior to her illness and had not had any recent vaccinations. She had no significant past medical or family history of note. However, the onset of her symptoms did correspond to her having chickenpox. She was subsequently found to be positive for HLA B51. In view of the ophthalmology findings and positive HLA B51, the little girl was admitted for an urgent MRI/MRI to exclude neuro- Behçets. This was reported as normal. She was treated with a three-day pulse of IV methylprednisolone and discharged on oral prednisolone 10mg OD (weight 33.4kg). At present Bechet’s retinal vasculitis remains high in the list of differentials for this little girl; however, currently she does not strictly meet the diagnostic criteria for Bechet’s disease. She has been commenced on a steroid sparing agent, azathioprine. Her follow-up plan is to be reviewed in the joint paediatric rheumatology and ophthalmology clinic in 1 months’ time. Case report - Key learning points Retinal vasculitis may occur secondary to a systemic disease or an infectious agent, or as an isolated retinal aetiology. Given that the differentials are vast, a detailed history and examination are important to identify signs and symptoms of systemic disease. Appropriate investigations should be chosen to help narrow the differentials and ensure pathology that could lead to significant morbidity and mortality is not missed. With a case such as this, close collaboration between the paediatric ophthalmologist and rheumatologist is paramount to ensure the best outcome for the patient. With regards to treatment, small case series have described a refractory nature of retinal vasculitis in paediatric patients. One study report that almost 80% of patients with paediatric idiopathic uveitis show manifestations of retinal vasculitis, which is associated with a lower probability of inflammation control resulting in a worse visual prognosis. Points for discussion

Background A two-dose hepatitis B (HBV) vaccine with an immunostimulatory adjuvant (HBV-ISS, Heplisav-B), was FDA approved in 2017 for adults 18 years and older. In randomized controlled trials (RCTs), HBV-ISS demonstrated a seroprotection rate (SPR) of 90–95% versus 65–80% for Engerix-B (HBV-Eng). No RCTs, however, included people with HIV (PWH), and the SPR and its predictors in this population are unknown. Methods This retrospective cohort study enrolled PWH ages 18 years and older without current HBV seroprotection at an HIV clinic at a tertiary care center. HBV seroprotection was defined as an anti-HBV surface antibody level >= 10 mIU/mL. Patients without follow-up titers after immunization were excluded. The primary outcome was the SPR, the proportion of patients with HBV seroprotection at any point following the first HBV-ISS vaccination. Results Among the 51 PWH included, 50 received 2 doses of HBV-ISS (1 patient who received 1 dose developed seroprotection) (Table 1). Median time to antibody titer measurement was 11 weeks (IQR 7–19 weeks). Median age was 59 years, 90% were men, and 96% had VL < 200. There were no pregnant or breastfeeding patients. The SPR was 82% (42/51) in the cohort, and 86% (38/44) when patients with significant non-HIV immunosuppression (decompensated cirrhosis, solid organ transplantation, active chemotherapy) were excluded. There were no significant differences in SPR based on age, sex, BMI, diabetes mellitus, chronic kidney disease, history of remote anti-HBV surface or core antibody positivity, or prior HBV vaccination (Table 2). Lower current and nadir CD4+ counts were associated with progressively lower SPRs (P for trend < 0.0001 for both) (Figure 1). Table 1. Baseline Demographics and Characteristics Table 2. Seroprotection Rate (SPR) by Variables of Interest Figure 1. Seroprotection Rate (SPR) by Current and Nadir CD4+ Count Conclusion The SPR from HBV-ISS in PWH appears comparable to the immunocompetent patients included in RCTs, especially when patients with significant non-HIV immunosuppression are excluded. The SPR demonstrated in this single-arm, retrospective study was higher than that of HBV-Eng in immunocompetent patients, and consideration should be given to establishing HBV-ISS as first-line HBV vaccination in PWH. Finally, SPR is significantly reduced in those with lower current and nadir CD4+ counts. Further research on the effectiveness of a repeat vaccination series or higher dosing in these subgroups is needed. Disclosures Jennifer Cocohoba, PharmD, AAHIVP, BCPS, Viiv (Grant/Research Support)

Objective Management of poor response and of long-term complications after bariatric surgery (BS) is complex and under-investigated. Indications and types of reoperations vary widely and postoperative complication rates are higher compared to primary BS. Benchmarking uses best performance in a given field as reference point for improvement. Our aim was to define ‘‘best possible’’ outcomes for elective secondary BS. Methods The establishment of benchmarks in secondary BS followed a standardized methodology, based on recommendations of a Delphi consensus panel of experts. This multicenter study analyzed patients undergoing elective secondary BS in 18 high-volume centers on 4 continents from 06/2013 to 05/2019. Twenty-one outcome benchmarks were established in low-risk patients, defined as the 75th percentile of the median outcome values of the centers. Benchmark cases had no: previous laparotomy, diabetes, sleep apnea, cardiopathy, renal insufficiency, inflammatory bowel disease, immunosuppression, history of thromboembolic events, BMI>50kg/m2 or age>65 years. Descriptive statistics, multivariate logistic regression and data visualization were performed using the R software. Results Out of 44’884 elective bariatric procedures performed in the participating centers, 5’328 secondary BS cases were identified. The benchmark cohort included 3143 cases, mainly females (85%), aged 43.8±10 years, 8.4±5.3 years after primary BS, with a body mass index 35.2±7kg/m2. Main indications were insufficient weight loss (43%) and gastro-esophageal reflux disease/dysphagia (25%). 90-days postoperatively, 14.57% of benchmark patients presented ≥1 complication, mortality was 0.06% (n = 2). Significantly higher morbidity was observed in non-benchmark cases (OR 1.36) and after conversional or revisional procedures with gastrointestinal suture/stapling (OR 1.7). Benchmark cutoffs at 90-days postoperatively were ≤5.8% re-intervention and ≤8.8% re-operation rate. At 2-years (IQR 1-3) 15.6% of benchmark patients required a reoperation. Conclusion Secondary BS is safe, although postoperative morbidity exceeds the established benchmarks for primary BS. The excess morbidity is due to an increased risk of gastrointestinal leakage and higher need for intensive care. The considerable rate of tertiary BS warrants expertise and future research to optimize the management of non-success after BS.

Background and Aims The efficacy and safety of intravenous ferric carboxymaltose (FeCarb) has been demonstrated both in patients with chronic kidney disease and dialysis, but its effects have not been evaluated in kidney transplant (KT) recipients. Method Retrospective study (2016-2018) of KT recipients who received FeCarb during the first 30 days after kidney transplantation (KT). Early efficacy was analyzed by evaluating the first determination of ferrokinetics and hemoglobin levels after administration and late efficacy with the determination >90 days post-administration. Safety parameters were also analyzed. Results Out of 283 KT performed, 77 recipients received one dose of FeCarb (52 received a 500mg dose and 25 a 1000mg dose) after a median of 6 days after the KT (IQR 3.5-9 days). 24 patients required transfusion after administration, 7 of them in the setting of concomitant event and 17 for non-response to FeCarb. Among the non-responders (n=17) there was a higher percentage of women, the initial hemoglobin was lower and they received a higher dose of FeCarb (Table). Responders (n=53) improved early and late ferrokinetic and anemia parameters (Figure). In the multivariate analysis adjusted by gender, controlled infection at the time of FeCarb administration, dose of FeCarb administered, immunosuppression, and previous treatment with erythropoietin, hemoglobin levels below 8 g/dL were associated with increased risk of transfusion after FeCarb administration (HR 11.30 [3.03-42.2]). Tolerability was excellent, with no immediate adverse reactions after FeCarb administration. 17 responders had a controlled infection at the time of FeCarb administration (median days under antibiotic treatment: 3, IQR 1-5). The infection did not worsen the response to FeCarb and no clinical impairment after FeCarb administration was observed. Conclusion: FeCarb administration in early post-transplant anemia is effective in patients with hemoglobin higher than 8g/dl and is not associated with increased risk of infection deterioration.

Background/Aims The role of gold changed from first line DMARD to use in cases where other options were limited, either due to contraindication or ineligibility for biologics. In Autumn 2019, IM gold was withdrawn by the manufacturer due to supply issues, without consultation of the Rheumatology community. As such, a group of patients with difficult to manage disease have lost a key DMARD. We aimed to assess the impact of the withdrawal of gold on the management of IA within Northumbria Healthcare Trust. Methods Retrospective case note review. Results We identified 37 patients on gold as of Autumn 2019; 16 for seropositive RA; 4 for PsA; 16 for seronegative RA and 1 for axial spondyloarthritis. 28 were taking gold monotherapy, with 3 receiving regular glucocorticoid in addition. Eight were taking gold in combination with a csDMARD and one in combination with rituximab. Data are currently available for 30 patients regarding the circumstances of gold initiation. Of these, all had received at least one alternative csDMARD which was either inefficacious or intolerable. Reasons for avoiding biologics were not documented in all cases; concerns regarding frequent chest infections were common and documented as a clear contraindication in 5. Follow up has been impacted by COVID-19; only 19 patients have had follow up within the last 6 months, 7 have not been followed up since gold cessation. Fourteen (37.8%) have commenced an alternative DMARD. Six of these have commenced a high cost drug; rituximab (3), adalimumab (2) or tofacitinib (1). Five have commenced hydroxychloroquine (with one subsequently switching to leflunomide),2 methotrexate and 1 minocycline. Seropositive RA and PsA patients are more likely to have commenced an alternative DMARD, 8/16 and 2/4 respectively; compared to 4/16 with seronegative RA. Of 23 patients who have not commenced alternative DMARDs, 17 have been reviewed following gold cessation; 3 were felt to need additional treatment; 1 has been deferred due to COVID-19 and 2 did not meet criteria for biologic treatment when assessed in early 2020 and subsequent follow up has been delayed. Fourteen patients were felt not to need an additional DMARD, although 1 required an increase in methotrexate and 6 continued co-prescribed DMARDs at the usual dose. Conclusion The majority of patients have not required additional treatment although for some patients this may reflect the fact that the COVID-19 pandemic has significantly restricted routine follow up. This unusual case of forced DMARD cessation highlights the fact that drug free remission is possible and the ongoing need for immunosuppression should be reviewed. This also raised the ethical question of weather it is right to cease the production of medication which for some patients may be the only effective treatment option. Disclosure J. Stanway: None. D. Walker: None.

Background/Aims Statins are associated with muscle symptoms, from myalgia with normal CK, to rhabdomyolysis. A sub-group have an autoimmune necrotising myopathy with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies. This can present variably, from mild self-limiting illness to severe myopathy unresponsive to statin withdrawal, requiring long-term immunosuppression. A study from New Zealand estimated the incidence of anti-HMGCR-associated myositis to be 1 in 90,000 statin users, and an incidence of 1 in 500,000 has been estimated in a US population. Anti-HMGCR antibodies were first reported in 2010. As they are new, and testing is not widely available, they may be under-recognised in the routine assessment of patients with myopathies. However, detection is important as prompt immunosuppression may be needed. Methods We compared the 2019 incidence of anti-HMGCR antibodies in Southern England from two different laboratory groups, utilising different testing criteria. The St George’s and Berkshire Surrey Pathology Services (StG/BSPS) laboratories serve a population of 3.25 million and test anti-HMGCR antibodies solely on clinician request. The Southampton laboratory serves a population of 2.33 million and tests anti-HMGCR as part of the immunoblot for all myositis-associated antibodies and where clinical details suggest myositis or ILD. Results In 2019, 14 tests were performed by StG/BSPS and 662 by Southampton, with anti-HMGCR positives of 5 (36%) and 28 (4.2%) respectively. Adjusted to include only the adult population, the incidence of anti-HMGCR antibodies is 1 in 514,000 in the StG/BSPS area versus 1 in 66,000 in the Southampton area. We estimate statins to be used in 308,000 adults in the StG/BSPS and in 220,000 in the Southampton areas, assuming treatment in 12% of adults and age demographics representative of the national population. This suggests an incidence of anti-HMGCR antibodies of approximately 1 in 62,000 statin users in the StG/BSPS area and 1 in 8,000 statin users in the Southampton area, though statin exposure was not confirmed in all positive cases. Preliminary data from 17 anti-HMGCR positive cases shows that 76% had taken statins, for an average duration of 5.84 years (range 0.75-16 years). Median peak CK was 6489 (range 241-27555). 76% required immunosuppression, of which 70% required two or more different treatments. Conclusion The 7.7-fold higher incidence from the Southampton laboratory reflects a proactive approach, selecting far more samples for anti-HMGCR assessment than specifically requested by clinicians. This demonstrates under-awareness of this antibody in routine care. We propose adoption of an algorithm to trigger more widespread testing for anti-HMGCR antibodies, to identify cases amongst those with statin-associated myalgia or myositis, and in others without statin exposure. This will lead to better understanding of the spectrum of clinical disease associated with anti-HMGCR antibodies, as well as early detection and treatment of those who develop a necrotising myopathy. Disclosure V.M.K. Joseph: None. E.C. Rose: None. M. Lloyd: None. C.J. Edwards: None. S.K. Amar: None. T. Forster: None. K.A. Smith: None. R.D. Wheeler: None. P.D.W. Kiely: None.

Glioblastoma is associated with severe and multifaceted immunosuppression affecting all immune organs. Immunosuppression in GBM is a critical barrier to the success of immunotherapies and patient survival. We demonstrated that immunosuppression in the GL261-model of experimental GBM presents with significant thymic and spleen atrophy, MHCII downregulation, presence of potent immunosuppressive factors in serum, and sequestration of T-cells in the bone marrow. Parabiosis studies determined that soluble factors mediate immunosuppression by inhibiting T-cell proliferation, thymic involution, and loss of peripheral T-cells. In contrast, bone marrow T-cell sequestration was not mediated through soluble factors. While the immunosuppression in GBM is severe, a causative link between each facet of immunosuppression and overall survival is lacking. We used two strategies to block T-cell sequestration into the bone marrow and evaluated the extent survival was impacted in experimental GBM. First, we evaluated the extent a novel and off-the-shelf combination immunotherapy that uses extended 1/2-life IL-2 and anti-PD-1 reverses bone marrow T-cell sequestration. Sham treatment or anti-PD1 monotherapy did not alter T-cell sequestration in the bone marrow and animals had no enhanced survival. Extended 1/2-life IL-2 monotherapy and combination strategy both prevented T-cell sequestration into the bone marrow. However, only combined therapy, which also prevented MHC class II downregulation, improved survival. Second, we determined that glioma-bearing adrenalectomized mice do not present with bone marrow T-cell sequestration. However, sera of glioma-bearing adrenalectomized mice is as immunosuppressive as glioma-bearing controls. Blocking bone marrow T-cell sequestration in the presences of serum immunosuppression led to no survival benefit in glioma-bearing adrenalectomized mice compared to controls. In short, bone marrow T-cell sequestration alone does not correspond with overall survival in experimental glioma. Importantly, a concerted effort to reverse MHC class II downregulation and define inhibitory circulating factors may have the highest impact in immunotherapeutic efficacy and improving patient survival.

Case report - Introduction Granulomatosis with Polyangiitis (GPA) is a rare small- to medium-vessel vasculitis associated with anti-neutrophil cytoplasmic autoantibody (ANCA). Its multi-systemic features include pulmonary, ear, nose, and throat (ENT), renal, and neurological manifestations. Its incidence is estimated to be 10.2 cases per million population. It is challenging to diagnose when its symptoms are treated in isolation from one another. This case highlights the difficulty in diagnosing GPA in a patient with respiratory symptoms during the Coronavirus Disease 2019 (COVID-19) pandemic and describes the challenges of managing it in the context of a subsequent COVID-19 infection as the mainstay of treatment remains immunosuppression. Case report - Case description A 78-year-old female non-smoker with a history of leg ulcers developed a 3-month history of cough and haemoptysis and was treated in primary care for suspected sinus and chest infections. She then presented to Accident and Emergency twice for the same symptoms and was discharged after having her antibiotics changed. 2 weeks later, she presented for the third time with cough, ongoing haemoptysis, conjunctivitis in the right eye, pain over the right side of her head, and discharge from her right ear. She was admitted as she was pyrexical, tachycardic and her CRP was 60. COVID-19 swabs were negative. ENT team recommended IV ceftriaxone and metronidazole for suspected orbital cellulitis. Blood cultures remained negative. CT sinuses with contrast showed right sided thrombosis of transverse sinus and bilateral mastoid effusion of the middle ear. Following neurology review, she was anticoagulated with dalteparin. A day later, she was transferred to the Respiratory ward and dropped her Haemoglobin level to 70. Her chest radiograph showed diffuse alveolar haemorrhage and CT images showed widespread bilateral peri-hilar consolidation. A rheumatology opinion was sought and vasculitic screen showed ANCA 268, and PR3 >177. Her urinary protein/creatinine ratio was elevated at 90. Rheumatology team confirmed multi-systemic GPA and recommended starting oral Prednisolone 60 mg daily. After the renal team was consulted, she was moved to a side-room and started on IV Methylprednisolone (pulsed with three doses), along with cyclophosphamide and rituximab. Dalteparin was discontinued. 2 days later, she desaturated, and became pyrexical. Repeat COVID-19 swabs were positive. Three Consultants agreed that Plasma Exchange and Non-Invasive Ventilation (NIV) would be inappropriate. A Do Not Attempt Resuscitation form was signed, and prognosis was discussed with the patient and her 78-year-old husband who requested to visit. Patient deteriorated and unfortunately died 6 days later. Case report - Discussion This case is interesting because it highlights the diagnostic challenge of GPA. Retrospectively, it may be noted that doctors persisted in treating suspected infection although the patient continued to deteriorate. However, a diagnosis should be re-considered if the patient does not respond to treatment and it is important to consider vasculitis as a cause of haemoptysis. Anticoagulation was started since the benefits were considered to outweigh the risks as her haemoptysis was of small volume. The patient soon developed pulmonary haemorrhage, so the risks of anticoagulation should not be underestimated in vasculitis. The Rheumatology team’s cautious approach to immunosuppression was in stark contrast to the renal team’s aggressive approach. The Renal team believed that concerns about protecting the patient from COVID-19 when she was negative from this infection should not take precedence over appropriate immunosuppression from a potentially fatal vasculitis. The patient was admitted at the start of the COVID-19 pandemic and was negative for COVID-19 on admission. She was nursed in a bay on the Respiratory ward where she later became COVID-19 positive. This raises questions about whether the earlier test was a false negative result or whether her infection was hospital-acquired. Infection control guidelines were changing rapidly at the start of the COVID-19 pandemic. The decision to avoid plasma exchange was based on the findings of the PEXIVAS trial. NIV was avoided as it required a full-face mask to minimize particle dispersion but would pose an asphyxiation risk as patient was coughing up blood. Finally, the team learnt to be flexible in these extraordinary circumstances when dealing with the end-of-life decisions of the COVID-19 positive patient. Although her husband was a vulnerable person because of his age, he was given the opportunity to visit while wearing Personal Protective Equipment and agreed to self-isolate for two weeks. Case report - Key learning points This case helped me appreciate the complexity of deciding to immunosuppress an already severely ill patient in the context of the COVID-19 pandemic. I recognised that the patient had a poor prognosis with or without immunosuppression and our role as healthcare professionals was to give her the best chance of recovery. The conference will allow me to interact with other colleagues and discuss what they would do in this situation as our Rheumatology and Renal teams had different approaches. After further reading on false negative results, we found that Johns Hopkins researchers found that testing people for SARS-CoV2 too early in the course of infection is likely to result in a false negative test even though they may eventually test positive for the virus. I have also learnt about the PEXIVAS trial which found that the addition of plasma exchange to standard therapy does not reduce the risk for all-cause mortality among patients with severe ANCA-associated vasculitis. Moreover, a reduced-dose regimen of glucocorticoids is non-inferior to a standard-dose protocol, while reducing the risk for serious infections. Diffuse alveolar haemorrhage (DAH) is not treatable with arterial embolization or bronchoscopic methods due to the diffuse nature of the bleeding. Extracorporeal membrane oxygenation (ECMO) has been used to support patients with DAH but the use of ECMO is controversial due to the need for anticoagulation. The conference will help me deepen my understanding of epidemic rheumatology which will be useful for my clinical practice going forward, especially if there is a second wave of the COVID-19 pandemic. I am keen to use this event to engage with other clinicians on immunosuppression in the context of infection so that I may confidently manage similarly complex cases in the future.

Case report - Introduction Primary Sjögren’s syndrome is a systemic autoimmune disease affecting the exocrine glands, commonly resulting in dryness of mouth and eyes. It can also rarely present with neurological symptoms most commonly peripheral neuropathies. The case highlights a rare case of sensory and motor neuropathy with some features suggestive of Sjögren’s syndrome as an underlying diagnosis. Case report - Case description A 54-year-old Caucasian lady was transferred from a local hospital for specialist neurology care. She described widespread paraesthesia over two months progressing to lower limb weakness worsening over a two-day period. Her symptoms further progressed to involve her arms and new blurred vision. On further questioning she reported previous severe mouth ulcers, possible genital ulcers and painful jaw swelling with long standing history of dry mouth. On thorough neurological examination, the positive findings were mild ptosis of the right eye, paraesthesia on palpation of face, upper limbs had a flaccid tone with reduced power and pseudoathetosis of outstretched arms, reduced proprioception, and absent reflexes. Lower limbs were more affected with worse power and absent proprioception. Schirmer’s test showed normal tear production but saliva production was reduced. MRI brain and spine were reported as pathological enhancement in both optic nerves, no obvious brain parenchymal abnormality, no obvious spinal cord abnormality. Lumbar puncture CSF pro 0.38, white cells 12 (poly 50%, mono 50%), red cells 3700, no organisms on gram stain, opening pressure 21.5 cmH2O. Sural nerve biopsy demonstrated profound loss of sensory axons, severe loss of large myelinated fibres in all fascicles with motor nerve involvement. Muscle biopsy demonstrated chronic neurogenic atrophy. Rheumatology screen showed positive anti Ro 52 antibodies (on an extended myositis screen). EMG demonstrated neurophysiological evidence of widespread marked loss of sensory axons in the upper and lower limbs and partial loss of motor axons in several lower limb territories. USS parotid glands showed some possibly mildly abnormal areas, minor salivary gland biopsy was normal. She received methylprednisolone, IV immunoglobulin and two courses of plasma exchange. Given some improvement following this treatment, further immunosuppression was felt to be appropriate. Initially Mycofenolate mofetil was started and Rituximab is now being considered. Case report - Discussion This case demonstrates a mixed neuropathy picture. Following thorough investigations, many differential diagnoses of mixed neuropathy were considered and excluded (e.g. Guillain Barre, Syphilis, MS, HIV, Hepatitis). Neurological symptoms can develop before the onset of sicca symptoms in Sjögren’s syndrome. With a positive Anti Ro52, xerostomia and clinical improvement with methylprednisolone and plasmaphereses it seems likely there is an underlying autoimmune diagnosis in this case and despite a normal biopsy she would meet the 2016 ACR/EULAR classification criteria for Sjögren’s syndrome. Case report - Key learning points Sjögren’s syndrome should be considered as a potential underlying cause in patients with a sensory ganglionopathy. Neurological symptoms can develop before the onset of sicca symptoms in Sjögren’s syndrome.

Background The European Society of Cardiology (ESC) guidelines for the diagnosis and management of pericardial diseases identify predictive factors of poor prognosis and advise either in favour or against hospitalisation accordingly. Our aim is to evaluate the adequacy of hospitalisation criteria in a cohort of patients presenting to the emergency department (ED) with acute pericarditis. Methods Retrospective analysis of patients admitted in ED with acute pericarditis, from 2009 to 2019. All patients were evaluated by a cardiologist during ED stay who decided if the patient was to be discharged or hospitalized. Hospitalized and discharged patients were compared regarding primary outcome, defined by a composite of: need for pericardiocentesis and/or cardiac surgery, pericarditis recurrence and all-cause death. Clinical decision was then counterpoised with ESC guidelines. Results A total of 192 patients were included in the analysis (aged 46±18.5 years-old, 83.3% male) of which 87 (45.5%) were hospitalized. A total of 25% registered the primary outcome, mainly due to acute pericarditis recurrence, occurring in 21.9%. Predictors of recurrence were: glucocorticoid therapy (OR=11.93, 95% CI 3.13–45.5, p Conclusions Discrepancy between current guidelines and clinical decision did not translate into a different outcome. Funding Acknowledgement Type of funding source: None

Background and Aims The recipients who have antibodies againts to donors’ HLA (Anti HLA- DSA) carrie a huge risk for allograf (AG) losing. In current study, it was retrospectively evaluated whether the live donor kidney recipients (LDKRs) under desensitization (DS) were exposed to more AG loss, lower AG survival and more complications. Method In 17 of 269 LDKRs had high anti-HLA DSA were found prior to kidney transplantation (KTX). DS was performed with plasmapheresis (PF) and rituximab (RTX) before KTX. In order to determine the risks of DS, LDKRs who had not PF for any reason, were admitted immediately before and after those with LDKRs under DS were used as controls (n: 31). Immucor™ luminex method was used for detecting the anti HLA DSA. DS was performed to the Rs who had more than 5000 MFI DSA against to at least one donor HLA locus with double check. Non-parametric Fisher’s exact test was used for statistical analysis because of distribution of our patients was heterogeneous. Results In 15 Rs had DSA more than 2 HLA loci (MFI range: 5880-21712), remaining 2 Rs had one HLA locus DSA (9959-7762). Mean PF number was of 7 before TX, while 3 after TX. RTX was used in 9 Rs (53%) before TX. KTX performed when anti DSA MFI below 2000 under triple immunosuppression plus anti-thymocitic globulin (ATG) induction therapy. In 4 Rs (13%) had DSA below 5000 MFI among controls (Cs). More female Rs (88% vs. 19%, p0.05), rate of indication biopsy (24 % vs 16 %, p>0.05), rate of CNI toxicity (5.5% vs. 6.5%, p>0.05) were indifferent. During whole follow-up period, creatinine levels and eGFR were compatible at both groups. Urinary infections were more frequent in Rs under DS (53% vs 6.5%, p Conclusion Although our results belong to a single center and also a small group, desensitization before kidney transplantation for high risk kidney recipients are seem to be useful, effective and successful procedure.

Background and Aims The reported incidence of lupus nephritis (LN) is approximately 6.1 cases per million population per year in Scotland based on Scottish Renal Registry biopsy data. Despite immunosuppressive treatment, approximately 10-30% of patients will progress to established renal failure (ERF) within 15 years. In December 2007, our unit moved from a protocol of Cyclophosphamide/ steroid induction with Azathioprine/ Prednisolone maintenance to Mycophenolate/ steroid induction and maintenance. We undertook this study to compare remission rates before and after this change. Method A retrospective electronic patient record analysis was performed for all patients in our centre with a documented native renal biopsy showing a histopathological diagnosis of LN, between 1 July 1993 and 31 December 2017. Repeat biopsies were excluded. Baseline demographics, histopathological class and first and second line induction and maintenance therapies were recorded. Endpoints analysed were; partial and complete response (as defined in KDIGO Clinical Practice Guideline for Glomerulonephritis 2012), time to achieve this response, relapse, progression to ERF and death. Results 120 patients who underwent a biopsy during the 24.5-year period received a diagnosis of lupus nephritis. 82.5% of patients were Caucasian. Median duration of follow-up was 72 months. 15% of patients died and 5% developed ERF within the follow-up period, representing one death per 56 patient years and one incident case of ERF per 168 patient years. There were 40 patients in the pre-December 2007 group and 80 in the post-December 2007 group. Those in the earlier group were younger, with a mean age of 35.4 years versus 44.8 years in the later group (p=0.002). 23% had class V in the earlier group compared to 15% in the later group (p=0.31). Proportions of female patients were 80% and 75% in the early and late groups respectively (p=0.54). Median creatinine was 106µmol/L in the pre-December 2007 group and 89.5 µmol/L in the post-December 2007 group (p=0.96). Patients in the pre- and post- December 2007 groups had comparable rates of complete response, at 72% and 71% respectively. However, those diagnosed before December 2007 were slower to respond, with a median time to achieve complete response of 10.5 months, compared to 6 months in those diagnosed after 1 December 2007 (p=0.007). Conclusion Following a change in our immunosuppressive induction regimen from Cyclophosphamide/ steroids to Mycophenolate/ steroids, our response rates have remained similar, however speed of attaining remission has improved.

Background and Aims Post-transplant lymphoproliferative disorders (PTLD) are a group of heterogeneous lymphoid proliferations in chronic immunosuppressed recipients of solid organ and hematopoietic stem cell transplantation. Due to rarity of this disease, retrospective studies from transplant centers have been the main source to provide knowledge and treatment guidelines, which are still in evolution. This study examined the clinical outcomes and identified the predictors of mortality in adult renal transplant recipients who developed PTLD. Method We have studied the incidence of PTLD in adult renal transplant recipients who were transplanted in our hospital from 1996 to 2019. Data was collected for demographics, transplant and immunosuppression history, EBV and CMV serostatus, diagnosis, treatment and outcomes of PTLD. We performed univariate and multivariate analysis to identify prognostic factors. PTLD was classified according to 2018 WHO lymphoma classification. Results Twenty-four patients (12 males and 12 females) were eligible for the analysis. Mean age at time of the transplant was 43.1 ± 16.9 years, with a time between grafting and PTLD of 66 months (IQR 36-98 months). Mean follow-up time was 87 months (IQR 61-117 months). 25% of patients received a living donor renal transplant. 12,5% of patients received induction therapy with thymoglobulin. Mean age at time of PTLD diagnosis was 48,8 ± 17,9 years. Five cases were from Epstein-Barr virus (EBV) mismatched (D+/R-) transplants and there was seroconversion at time of PTLD diagnosis. 25% of patients had central nervous system involvement. 19 patients have monomorphic PTLD and the most common histological diagnosis was diffuse large B cell lymphoma. We identified that age >30 years at time of the transplant was predictor of mortality (HR 33.01; 95% CI: 3.24-336.14; p=0.003). Surprisingly, presence of B symptoms at time of PTLD diagnosis confer a better prognosis (HR 0,143; 95% CI: 0,035-0,579; p=0.006). All cases were managed with reduction in immunosuppression and converted to everolimus. 8 patients were treated with rituximab and there was no significant difference in the survival of these patients. By the end of follow-up, 7 patients went into remission, 1 returned to chronic dialysis, and 16 patients died (15 of them due to the disease). Mean time between PTLD and death was 3 months (IQR 1-6 months). Conclusion PTLD is an infrequent disease with a poor prognosis in renal transplant patients. Some cases have a close relationship with EBV, but it can also develop in the absence of the classical risk factors. The factor affecting mortality in our population was age >30 years at time of the transplant. Presence of B symptoms at time of PTLD diagnosis seems to confer a better prognosis probably due to early investigation and diagnosis of the disease.

Background and Aims Tunneled central venous catheter (T CVC) use is rising among patients undergoing chronic hemodialysis (HD) and non-tunneled (NT) CVCs are often used for HD initiation in late referral chronic kidney disease (CKD) or acute kidney injury (AKI). Catheter-related bloodstream infections (CRBSI) are a major complication of CVC use. This study examines potential patient- and CVC- related factors associated with CRBSI incidence and its microbiological features. Method In this retrospective single-center study, 413 patients undergoing an extracorporeal treatment (HD or Plasma Exchange) between February 1st 2014 and January 31st 2017 with 561 CVCs were recruited. Clinical data at study entry and CVC type are summarized in table 1. All bloodstream infections (BSI) occurring during the observation period were recorded and classified into CRBSI or non-CRBSI (nCRBSI), and their infecting agents collected. An incidence rate ratio (IRR (95% CI)) was calculated to assess the association between CRBSI incidence rate (IR), expressed as events/1000 catheter-days, and each clinical variable or CVC type. Significant associations at the univariate analyses were investigated with multivariate cox models. Results During a cumulative follow-up time of 66686 catheter-days, 54 (IR: 0.81) CRBSI and 30 (IR: 0.45) nCRBSI events occurred. CRBSI had higher frequency of GRAM+ bacteria compared with nCRBSI (70% vs 33%, p At the univariate analysis, male sex, age Conclusion Patients affected by AKI and use of NT or Femoral CVCs are independently associated with CRBSI risk.

Background and Aims The role of polyomaviruses (PyV) in malignancy is controversial, this can be demonstrated in three ways; Firstly, hit and run mechanism where polyomaviruses contribute to the early phases of oncogenic progression. The second way, where PyV act as a passenger as polyomaviruses neither necessary nor contribute to the oncogenic progression. The third way, where PyV acts as (bystander) as PyV is not related to the malignancy, but PyV could be detected in the anatomically connected sites or neighbouring cells. BKV has been classified as a possible carcinogenic to humans (2b) as there is sufficient evidence that it is carcinogenic to animals, however, BKV carcinogenicity evaluation to humans was inadequate. There are inconsistent data regarding the contribution of BKV to tumors that occur in both animals and humans. Method Retrospective analyses of 492 consecutive renal transplant recipients in a single-center, 2010-2018. Data Source: prospectively managed electronic patient records. Malignancy data in both control and BKV infected groups were assessed. Results A total of 492 cases were studied, were categorized into 2 groups the BKV infected group (n:73) patients and BKV non-infected group (n: 419) patients, then an assessment of different malignancies in both groups. The BKV infected group had 15 cases out of 73 who had malignancy, while the BKV non-infected group had 28 cases out of 419 totally (Table 1). The association between malignancy in BKV was statistically significant (P-value of 0.038). Moreover, the risk factors involved in the development of malignancy in renal transplant recipients were older age, BK virus infection and maintenance immunosuppression agents (Table 2). Lastly, Logistic regression analysis was used to assess predictors of malignancy among renal transplant recipients. For every one-year increase in age among renal transplant recipients, the odds of having a malignancy increase by 4.6% (p=0.003). Meanwhile, there is a 4 times increase in the odds of having malignancy for recipients who are BK virus-positive vs. those who are BK virus negative (p=0.001). Furthermore, there is a 10 times increase in the odds of having malignancy for recipients who are on sirolimus as a maintenance immunosuppressant vs. those who are on TAC/PRED/MMF (p=0.007). Conclusion Our study highlights the statistically significant correlation between BK virus infection and the development of malignancy in renal transplant recipients. However, statistical correlation doesn`t mean causation which makes the potential oncogenic role of BKV is unclear. Also, there is increased reporting of malignancy in patients infected with BKV. Increased vigilance is required for early detection of malignancy in patients infected with BKV not only the patients who are heavily immunosuppressed.

Background and Aims There are many barriers to kidney transplant and one of them is presence of donor specific antibodies (DSAs) in the recipients. Presence of strong DSA is considered a relative contraindication for kidney transplantation, however, if DSAs are of weak to moderate then desensitization is attempted in many centres with good success rate. Desensitizing such patients can be an acceptable approach to increase the donor pool and facilitating transplants. This is a retrospective analysis of patients who underwent desensitization at our centre after availability of luminex single antigen (LSA) assay Method Between April 2014 and December 2018, 825 patients underwent kidney transplantation at our centre. Patients who were CDC negative but positive FCXM were further analysed with LSA to know the presence and strength of DSAs. Our protocol for desensitization consisted of plasmapheresis (PP) 1.5 volume by double filtration on alternate day and low dose IV IG 100 mg/kg after each PP. Whenever MFI was Results Out of 825 patients, 15 underwent HLA incompatible transplants, of which, 8 were males. All patients were first transplant and 11/13 had history of some sensitizing events in the form of blood transfusion and/or pregnancy. The mean dialysis duration was 8.6 ±14.6 months. FCXM was positive in all the patients with 5 patients had T cell flow positive, 8 had B cell flow positive and 2 had both T & B cell FCXM positivity. Most patients had weak to moderate positive flow cross match. On further evaluation by LSA, all these patients had DSAs, with 3/15 had MFI 2000, out of which one patient had MFI of 7195 and six patients had multiple DSAs. These patients underwent desensitization with PP and IVIG and the end point of treatment was either MFI < 1000 or FCXM negative. Post- transplant DSAs were done in patients with high MFI or clinically indicated. Two patients had increase in post-transplant DSA titres requiring post-transplant plasmapheresis. The mean follow up was 29±6 months. On follow up, only 1 patient developed borderline cellular rejection one year after transplant, which responded with pulse steroids. Three patients had biopsy for asymptomatic rise in creatinine but it showed patchy ATN with no evidence of rejection.. One patient developed transient CMV viremia, one patient developed lymph node tuberculosis (TB) and two patients had UTI, all of them responded to treatment. There was no graft or patient loss till last follow up. Conclusion This study shows that HLA desensitisation is feasible and successful in if patients are selected carefully and evaluate thoroughly. HLA incompatible transplant can provide a new lease of life to those patients who would otherwise not get a kidney due to lack of paired exchange and deceased donor program

Background and Aims TOMOGRAM, multicenter study founded by DESCARTES ERA/EDTA WG, aims to identify transcriptomic and genomic signatures of operational tolerance (OT) in recently identified cohort of OT kidney transplant recipients. Method RNA sequencing of peripheral blood was evaluated in 15 OT patients recently identified by TOMOGRAM consortium in 8 European countries, 23 stable patients (≥ 15 years on immunosuppression, STA), 14 CABMR patients (≥ 1 year, CR), 14 non-transplant CNI-treated patients and 14 healthy controls (HC). Differential expression was performed using DESEq2 and gene annotation analysis using Enrichr. Besides immunosuppression unadjusted model, robust negative-binomial regression model was created to adjust for immunosuppression intake. The models was trained on homogeneous group of STA patients. Results Using model unadjusted for immunosuppression, no differences in transcriptomic profiles between OT, STA and HC groups were identified. Nine transcripts were upregulated and 2 downregulated in OT compared CR group. The number of deregulated transcripts substantially increased when the model was adjusted for immunosuppression. Gene annotation analysis of top ranked deregulated 1109 transcripts (FC>2, adjusted p value 0.89) were used in PCA analysis (ADGRG3, ATG2A, GDPD5, IL16, MX2, SLA2, PRKD2, SLIRP, GNLY, SRCAP, ARGHAP9, IGHM, CD5). The high probability of OT signature was found in a single STA patient. Conclusion Contrary to previous reports which pointed out towards naïve B cell signatures, unique OT patients exhibit other specific immunosuppression-independent transcriptomic profiles.

Background A presentation of acute kidney injury (AKI) in a patient with a longstanding diagnosis of SLE nephritis was challenged following unexpected renal biopsy and immunology resulting in a diagnosis of primary Sjögren's Syndrome (pSS) related fibrillary glomerulonephritis (FGN). Methods A 62 year old Caucasian female presented with AKI and infected leg ulcer. Previously diagnosed with SLE (1996), anti-phospholipid syndrome and non-biopsy proven lupus nephritis (LN), CKD stage G2/3 she was on Hydroxychloroquine and lifelong anticoagulation. Examination revealed bilateral pitting oedema up to knees and a large non healing skin ulcer to left knee. Investigations showed new anaemia (Hb 75g/dl, MCV 94), lymphopaenia, urea- 25 (9.8), Creatinine- 280 (97), urine protein 6.88g/24 hr. USS KUB, ECHO, CXR, virology screen, PET CT were unremarkable. Immunology studies revealed ANA 1:160, anti-Ro, anti-La, but normal DsDNA and C3, C4. In the light of reported sicca symptoms and serology the diagnosis was revised to pSS. Renal biopsy was initially reported as diffuse lupus nephritis (Class IV) with crescents, and focal weak mesangial IgG and C3 but no glomerular deposits. Electron microscopy (EM) demonstrated abundant mesangial and intramembranous deposits with a fibrillary substructure diagnostic of FGN. Immunosuppression with pulsed intravenous (IV) methylprednisolone and IV Cyclophosphamide were given. She developed acute arterial intercostal bleeding at biopsy site and further significant lower gastrointestinal bleeding unamenable to endoscopic therapy or embolisation and the patient died. Results This case highlights the importance of ensuring that serology is interpreted correctly alongside histopathology and urinalysis in the diagnosis of CTD related renal disease. PSS related nephropathy is seen in less than 10% of patients. Tubulointerstitial nephritis (TIN) accounts for 2/3 of patients and glomerulonephritis (GN), typically membranoproliferative GN (MPGN) for most others. FGN in pSS is very rare, with only 3 reported cases to date. Like lupus nephritis, FGN can present with AKI, hypertension and nephrotic range proteinuria. However, renal biopsy proves invaluable in differentiating between the conditions. In FGN characteristically on biopsy disorganised, non-branching fibrils are seen in all glomerular compartments and are negative for congo red stain further differentiating from amyloid FGN. Immunofluorescence microscopy shows uniform staining of the fibrils for immunoglobulins (mostly subclass IgG4). FGN has a poor prognosis with patients developing severe chronic renal failure despite immunosuppression. Conclusion Considering surprising investigation results, it is crucial we rechallenge the validity of longstanding diagnoses as highlighted by our case. In proven pSS with systemic features we recommend screening all patients for renal disease annually including serum electrolytes, urine dipstick, protein creatinine ratio and pH. If abnormalities are identified, renal US and consideration of biopsy is crucial in establishing aetiology as management and prognosis differs between subtypes. Disclosures C. Amoasii None. R. Benson None. J. Harper None. D. Mewar None.

Background Systemic lupus erythematosus (SLE) or lupus (Latin for wolf) is a rare multi-system autoimmune disease that has usually presented by the fifth decade, with a seven-fold higher incidence in females, especially of Afro-Caribbean descent. It is a recognised cause of pyrexia of unknown origin (PUO) though infection and malignancy are far commoner causes. Lupus nephritis (LN) can be life-threatening and affects nearly one-third of patients. We highlight a surprising case of late-onset SLE in a 65-year-old Caucasian man that presented with PUO and early LN. Methods Our patient was known to have atrial fibrillation, hypertension and previous obstructing renal calculus and presented to the Emergency Department with two weeks of right flank pain and fevers. He required critical care admission due to haemodynamic instability. CT excluded obstructive uropathy but a complex right renal cyst was present with mild inflammatory stranding. Bloods showed new neutrophilia (8.31-9.50 x 109/L), anaemia (haemoglobin 93 g/L), thrombocytopenia (platelets 90 x 109/L) and acute kidney injury (creatinine 128 μmol/l from 90 μmol/l baseline). CRP persisted above 110 mg/L. Liver function and ferritin were normal. Despite escalation of antibiotics he remained febrile, creatinine peaked at 291 μmol/L with raised urine protein:creatinine ratio (PCR) of 384 mg/mmol. Repeated septic screens and blood-borne virus tests were negative. Further CT showed mild ascites and pleural effusions. Transthoracic echocardiogram revealed a small pericardial effusion only, and pleural aspirate was a transudate, without malignant cells. Results There was clinical improvement after three weeks despite persistent fevers and he was discharged. However, readmission within three days necessitated inotropic support. After stabilisation, he was transferred under Infectious Diseases in a tertiary hospital. Shortly afterwards, the autoimmune screen showed positive anti-nuclear antibody (ANA), with positive Crithidia luciliae IgG double-stranded DNA (dsDNA) and titres >379 IU/mL. Concurrent hypocomplementaemia (C3 0.22 g/L, C4 0.03 g/L) raised the possibility of LN with SLE and renal biopsy demonstrated class 3 LN. Prompt treatment with intravenous glucocorticoids and mycophenylate mofetil (MMF) resulted in an excellent recovery. Almost a year later, he is taking MMF 1g twice daily with prednisolone 10mg daily. His creatinine is stable at 110 μmol/L, urine PCR around 300 mg/mmol and complements have normalised, despite persistent dsDNA titre of 150 IU/mL. He continues driving taxis and reports a good quality of life. Conclusion There was low suspicion of SLE in this case given the absence of typical symptoms and considering his age, gender and ethnicity. A literature review of male patients with SLE suggested tendency for later-onset and a worse prognosis. There appears to be less LN but when present requires prompt immunosuppression as occurred in this case. Currently, the oldest documented male patient with both SLE and biopsy-proven LN at diagnosis was 74 years old. Disclosures M. Chakravorty None. R. Sandler None. A. El-Nayal None.

Cestodes are emerging agents of severe opportunistic infections among immunocompromised patients. We describe the first case of human infection, with the recently-proposed genus Versteria causing an invasive, tumor-like hepatic infection with regional and distant extension in a 53-year-old female kidney transplant recipient from Atlantic Canada.

Background The aim of this study was to determine the disease phenotype, evolution and therapeutic needs of de novo inflammatory bowel disease (IBD) in transplanted patients. Methods A retrospective single center study that included all patients who developed IBD after solid organ transplantation in a tertiary hospital. Data collected included transplant-related variables, IBD phenotype, course of the disease and its treatment. A control group of non-transplanted IBD patients was randomly selected. Results We included 17 post-transplanted IBD patients and 57 non-transplanted IBD patients. Post-trasplanted patients were older at diagnosis, had greater colonic involvement, with an inflammatory behaviour, absence of perianal involvement and extraintestinal manifestations compared to control group (Table 1). The most common immunosuppression regimen was tacrolimus+mycophenolate mofetil (MMF)+prednisone and the most frequent change after diagnosis was the switch of MMF for azathioprine. De novo IBD patients required less biological therapy than the control group (11.8 vs 42.1% p 0.02) and none required surgical intervention compared to 35.1% in the control group (p 0.002). Multivariate analysis carried out on the total population showed that active smoking, perianal disease and extraintestinal manifestations were associated with a greater need for biologics, while the only factor that influenced surgical risk was stricturing and penetrating behaviour of Crohn′s disease. Conclusion De novo IBD after solid organ transplantation has a favorable course, predominating the inflammatory behaviour and requiring less biological therapy and surgical interventions. The absence of extraintestinal manifestations and perianal disease stands out.

Background Trimethoprim-sulfamethoxazole (T/S) and levofloxacin are considered first line agents for the treatment of Burkholderia cepacia complex (Bcc). Combination therapy (CT) is frequently utilized despite limited clinical evidence supporting this. The objective of this study is to compare outcomes associated with different regimens for the treatment of Bcc infections. Methods This is a retrospective cohort study in non-cystic fibrosis adult patients with infection caused by Bcc from 2015 to 2019. The primary outcome is the composite of overall treatment failure defined as clinical failure, microbiologic failure, or mortality at 30 days. Secondary outcomes include mortality, clinical failure, microbiological failure, development of resistance, recurrence, and safety. Comparisons were performed using Chi-squared or Fischer’s exact test for categorical variables and Student’s t test or the Mann-Whitney U test for continuous variables, as appropriate. Multivariable logistic regression analysis was used to identify independent risk factors for overall treatment failure. Results Sixty-eight patients were included, 50 (74%) received monotherapy (MT) and 18 (26%) received CT. MT regimens included meropenem (n=19), ceftazidime (n=15), T/S (n=10), and other (n=6). Various combination regimens were utilized. MT recipients were significantly older, more likely to have renal disease, less likely to have an immunosuppression, and had a higher severity of illness. The most common site of infection was respiratory (78%). No difference was found for overall treatment failure between MT and CT (36.0% vs. 38.9%; p=0.947). No differences were found in the secondary outcomes (Table 1). Overall treatment failure did not differ by treatment regimens utilized. On multivariable analysis controlling for age, renal disease, CCI, immunosuppression, ICU admission, SOFA score, and receipt of MT, only SOFA score was associated with treatment failure [OR 1.43 (95% CI 1.15 to 1.77); p=0.001] and not MT [OR 1.22 (95% CI 0.25 to 5.97); p=0.808]. Table 1: Treatment Outcomes – MT versus CT Conclusion There were no differences in outcomes between MT and CT groups for the treatment of Bcc infection. Treatment outcomes appeared to be driven primarily by disease severity. Additional studies are needed to identify the optimal treatment regimens. Disclosures All Authors: No reported disclosures

Background There has been a global increase in people who are intravenous drug user, diabetic, and elderly (aged greater than 65 years). These characteristics may alter the incidence of new diseases and potentially affect how diseases are diagnosed. As such this study’s purpose was to investigate baseline characteristics of patients with pulmonary blastomycosis. Case studies for Blastomyces have demonstrated positive cultures in 72% to 87% of patients. Therefore data will be analyzed to determine if there is any significant difference in culture results. Methods This study was a retrospective single-center ecological study. Patient charts were identified via ICD code search for blastomycosis. All protected health information was de-identified following data collection. Results 32 patients were identified with either pathology or culture proven blastomycosis. 8 patients (25%) had positive fungal cultures for blastomycosis. The average age of patients with pulmonary blastomycosis was 59.5 years old with 11 elderly patients (34%). There were 11 females (34%); 2 with hepatitis C (6%); 12 with diabetes (38%); 10 with immunosuppression (pancytopenia, chronic steroid usage, organ transplant, cystic fibrosis) (32%); 9 with COPD (32%); 21 with Tobacco abuse (67%); 7 with cancer (22%); 7 with work exposure (working around turned dirt or indoor mold) (22%) and 1 with opiate use (3%). No significant difference was found for culture results. Baseline Characteristics Culture Characteristics Conclusion Our culture results were exceedingly low in part due to some samples not being collected for fungal culturing and having to send-out the samples. The average age was consistent with the endemic region of Tennessee around 59 the previous 10 years.. 2/3 of the patients were tobacco abusers which may have contributed to some impaired ability to clear the fungal spores. Less than half of the patients were elderly, diabetic, immunosuppressed, or intravenous drug users therefore endemic inoculation may still be the main cause. Disclosures All Authors: No reported disclosures

Background Immunosuppression during liver transplantation (LT) enables the prevention and treatment of organ rejection, but poses a risk for severe infectious diseases. Antimicrobials are often required for patients after LT. Recently, the genomes of multiple microorganisms have been detected in blood, which is essentially sterile. Immune modulation and antimicrobials affect the blood microbiome. Thus, determining the impact of immunosuppression and antimicrobials on the microbiome may be important to understand immunocompetence, predict clinical adverse events after LT such as acute cellular rejection (ACR), and treat infectious diseases. Methods Fifty-one patients who received LT at Nagoya University Hospital from 2016 to 2018 were enrolled. Plasma samples were retrospectively collected within a week after LT, 4±1 weeks after LT, 8±1 weeks after LT, and within 2 days after a positive blood culture. A total of 111 plasma samples were analyzed using shotgun next-generation sequencing (NGS). Sequence data were imported into the custom-made analysis pipeline PATHDET. Results The relative abundance of Anelloviridae, Nocardiaceae, Microbacteriaceae, and Enterobacteriaceae significantly changed during the postoperative period (figure 1). Microbiome diversity was higher within a week after LT than at 8 weeks after LT. Antimicrobials were significantly associated with the microbiome of LT recipients. In addition, the proportion of Enterobacteriaceae was significantly decreased (figure 2) and the plasma microbiome diversity was significantly higher in patients with ACR than in non-ACR patients. Finally, sequencing reads of bacteria isolated from blood cultures were predominantly identified by NGS in 8 of 16 samples (figure 3), and human herpesvirus 6 was detected as a causative pathogen in one recipient with severe infectious diseases. Change in the relative abundance of each microorganism at the family level of taxonomic hierarchy in plasma samples after liver transplantation Comparison of the plasma microbiome at the family level in patients with and without acute cellular rejection Relative abundance of microorganisms at the species level in plasma from patients with positive blood cultures Conclusion The metagenomic NGS technique has great potential in revealing the plasma microbiome and is useful as a comprehensive diagnostic procedure in clinical settings. Temporal dynamics of specific microorganisms may be used as indirect markers for the determination of immunocompetence and ACR in LT recipients. Disclosures All Authors: No reported disclosures

Background Therapeutic aims in IBDs are to induce remission through rapidly effective treatment. Conventional therapeutic methods including immunosuppression have been available for more than half a century with biological therapies the treatment of choice in patients who fail immunosuppressive drugs. There has been little attempt to longitudinally examine the differences in biopsychological factors and their associations with treatment modalities in IBD patients. Methods 50 IBD participants (24 UC, 26 CD) in clinical remission were followed for 12 months. Complete longitudinal datasets including demography, disease status (HBI, Mayo score), monthly stool and blood samples for inflammatory biomarkers, monthly validated scores of psychological state, baseline physiological state and autonomic function were collected for analysis of association. Microbiome analysis was performed using V4 16SrRNA for identification of microbial phylogenetic relationships. Patients were grouped on whether or not they were in remission on biological agents. Results CD: There was a larger magnitude of change in linear trends of anxiety (p = 0.007) in CD patients on non-biologic treatment. Quality of life (QOL), health-related quality of life (HRQOL) and faecal calprotectin measures were similar regardless of treatment. Longitudinal quadratic trends of CRP were significantly different between the two (p = 0.039) with the larger magnitude of change in non-biologic groups. CD patients had similar microbial profile when compared between two treatment groups. UC: Similar distributions of longitudinal psychological measures were found in two treatment groups, although results suggested significant linear trend (p = 0.019) in QOL scores but not with HRQOL. Faecal calprotectin had significant longitudinal linear trend (p = 0.016) with significant interaction between biologic therapy and this trend (p = 0.023). CRP had significant quadratic trend (p = 0.005) with strong interaction between biologic therapy and this trend (p = 0.009). Microbial α diversity was significantly different between two groups of treatments (Shannon; p = 0.041, evenness; p = 0.045) with biologic group having more diverse and more even microbial community. Conclusion Baseline biological and psychological factors were mostly similarly distributed between the two treatment options in remissive IBD patients, however biological therapy significantly influenced longitudinal trends of some psychological, inflammatory and microbiome dynamics, especially in UC. This suggests an underlying interrelationship between mode of treatment and biopsychological trajectories which might overshadow response to the treatment, requiring further assessment.

Recent studies demonstrate the potential role of the microbiome in immune-oncology, revealing specific microbial taxa can augment the effects of various therapeutic modalities against tumors. Gut dysbiosis, a disequilibrium in the host’s bacterial ecosystem, can potentially lead to overrepresentation of some bacteria and favor chronic inflammation and immunosuppression. However, the effects of microbial dysbiosis on non-gastrointestinal cancers in particular gliomas are unknown. Here, we explored the effects of glioma and Temozolomide (TMZ) on the fecal microbiome (FM) in mice (n=24) and FM and metabolome in humans (n=40). Aged C57/B6 mice were implanted with Gl261 tumor cells or vehicle and were assigned to one of the following treatment (oral) groups: vehicle, 5mg/kg TMZ or 25mg/kg TMZ beginning 14 days after surgery for 3-weeks following a 5 day on/2 day off treatment. Fecal samples were collected prior to surgery, at treatment initiation and weekly thereafter until sacrifice and sequenced for 16s RNA. Fecal samples were collected from humans with newly diagnosed glioma before resection, chemoradiation, and after chemoradiation (16s RNA, metabolomic, neurotransmitter analysis). In mice, FM beta diversity was significantly altered with glioma (p=0.003) while the alpha diversity remained unchanged. At a genus and family level analysis the relative abundance of Bacteroides (p=0.01) and Bacteroidaceae (p=0.02) was increased. Beta diversity of mice receiving 5mg/kg TMZ changed from baseline (p=0.02). Collectively, this suggests that glioma alters the FM, to what consequence remains to be explored. Alpha (Observed OTUs, p=0.029) and beta diversity (p=0.034) differences in mice correlated with survival (< 25 - >25 days). In humans, norepinephrine and 5-hydroxyindoleacetic acid were significantly lower in glioma patients at diagnosis compared to controls. Our findings demonstrate for the first time the relationship between glioma and the gut-brain axis. Understanding alterations in the FM in glioma patients may allow novel interventions and should be further investigated.

Immunotherapy has failed to improve the overall survival (OS) of adults with GBM in all phase III clinical trials to-date. Somewhat less appreciated is that, de novo GBM is a disease associated with a median age of diagnosis at 64 years old. Because of the strong association between advanced aging and human subjects presenting with GBM, we further investigated our previously described observation of a higher mortality rate in elderly C57BL/6 wild-type (WT) mice with intracranial GL261 as compared to young counterparts after treatment with radiotherapy (RT) and anti-PD-1 (PD1)/IDO1 enzyme inhibitor (IDO1i) (Ladomersky et al., 2018; Clinical Cancer Research). Since immunosuppressive IDO1 expression significantly increases in both the mouse and human brain during advanced aging (Ladomersky et al., 2019; Frontiers in Pharm.), we decided to study how IDO1 and aging interact during immunotherapy of GBM. We found that the pretreatment effects of an IDO1 enzyme inhibitor improve OS in young but not elderly WT mice with intracranial GL261 (n=12–15/group; p< 0.05). Strikingly, in the setting of advanced aging, IDO1-/- mice with GBM show improved OS as compared with WT mice (p< 0.01) independent of treatment with an IDO1 enzyme inhibitor. Similarly stunning, 74–80 week old IDO1-/- mice with GBM treated at 14 days post-ic. with RT and PD1/IDO1i survive significantly longer as compared to elderly WT mice administered the same treatment (n=20–22/group; p< 0.05). These results collectively suggest that, the therapeutic effects of IDO1 enzyme inhibition is less effective in the setting of old age, and provides rationale for the development of new approaches that inhibit IDO1-mediated immunosuppression independent of its association with enzyme activity for eventually improving immunotherapeutic efficacy in human subjects with malignant glioma.

Background Juvenile osteochondritis dissecans (JOCD) is a condition of bone and cartilage lesions. Contributory factors may include ischaemia, trauma, genetic or biomechanical factors such as abnormal joint loading. Children and young people (CYP) with juvenile idiopathic arthritis (JIA) have low physical activity levels, present with joint abnormalities and are exposed to immunosuppression including steroids which may cause reduced bone density. Here we describe JOCD in CYP with JIA in our service. Methods Retrospective reviews of case notes were conducted for current CYP with JIA in our service with known JOCD, detailing: JIA diagnosis Age & BMI at diagnosisSymptom duration pre-diagnosisManagement (including steroids)JOCD diagnosis Age & BMI at diagnosisImagingManagement Results Table 1 summarises the results. Twelve (n = 10 female) CYP in our cohort of 270 had JOCD with 20 lesions diagnosed on magnetic resonance imaging (MRI). Polyarticular (n = 4) and extended oligoarticular (n = 5) were the commonest JIA sub-types with all CYP receiving systemic therapy and 75% (n = 9) requiring more than one biologic. Mean symptom duration before JIA diagnosis was 6 months (range: 1-24 months) with a mean age of 6.5 years (range: 1.5-13 years). Mean time to JOCD diagnosis was 5.5 years (range: 1.5-10.25 years) with a mean age of 12 years (range: 8-17 years) and 7 CYP having a high BMI (>85th percentile for age). The mean number of previous steroid injections per JOCD joint was 4 (range: 0-17) compared with 3 (range: 0-8) in the non-JOCD joint. Talar dome lesions (n = 9) were commonest, followed by femoral condyle (n = 4 medial, n = 3 lateral). Initial management was conservative, with half (n = 10) requiring surgery. P09 Table 1 Conclusion This review identifies that 4% (n = 12/270) of our CYP with JIA have known JOCD, compared with 0.03% (n = 29/100,000) of the general population. Risk factors appear to be polyarticular disease, exposure to ≥ 4 steroid injections per joint, biologic-resistant disease and high BMI with low physical activity. Where CYP with JIA report symptoms which do not fit an inflammatory pattern there should be a low threshold to consider JOCD, with prospective research needed to better understand the relationship between JOCD and JIA. Conflicts of Interest The authors declare no conflicts of interest.

Introduction Interstitial lung disease (ILD) is a progressive fibrotic disease of the lung parenchyma. The lungs are the most common site in rheumatic diseases. ILD may be idiopathic or caused by connective tissue diseases, rheumatoid arthritis, drugs, and infection and radiation therapy. The severity of lung involvement may vary considerably, and, in some cases, it can lead to irreversible fibrosis leading to respiratory failure and eventually death. Although progress has been made in understanding of the disease, there are still significant challenges with the diagnosis and treatment of ILD. This case illustrates the diagnostic and treatment dilemmas. Case description 67-year-old gentleman presented with a 4-year history of gradual onset of shortness of breath and dry cough with worsening over 18 months. Additionally, he developed ENT problems including nasal obstruction, polyposis, intermittent crusting with epistaxis and change in voice. He was treated with nasal douches, intermittent short courses of Prednisolone and antibiotics. He then developed joint pains with stiffness and weight loss. He had no other features of CTD or vasculitis. He was a BT Telecom office worker with no exposure to environmental agents, no family history and was an ex-smoker. Other medical history included type 2 diabetes and benign prostate hypertrophy. He was on metformin, finasteride, tamsulosin, fluoxetine and omeprazole. He had grade 2 finger clubbing with inspiratory bibasal crepitations. There was mild joint synovitis and systemic review was otherwise unremarkable. CT scan showed interstitial lung disease with UIP pattern. Initial lung function tests showed normal spirometry with TLCo 84% and KCO 86% predicted. Bloods revealed ACE 100, RF 16, MPO-ANCA 6.0, Eosinophilia 0.82 and CRP 7. A CT scan of the sinuses revealed bilateral ethmoidal polyps and moderate deviation of the nasal septum to the right. Initial treatment with glucocorticoids improved his joints, ENT symptoms significantly and respiratory symptoms marginally. However, his breathlessness and cough deteriorated over the next 6 months alongside lung function and DLco. Repeat CT scan showed progression of ILD with interval worsening of the honeycomb with reducing lung volume. He was tried on MMF but unfortunately deteriorated rapidly which led to hospital admission. CT scan showed new ground glass changes; it was thought to be acute exacerbation of underlying ILD with possible super added infection. He received high dose steroids and antibiotics with no improvement. Serial CXR showed rapid progression consistent with diffuse alveolar damage and he died 8 days after hospital admission. Discussion This case wasn’t straightforward. It was difficult to make a unifying diagnosis based on clinical presentation and the investigations. Given the predominant ENT and respiratory symptoms with low levels of MPO the most likely unifying diagnosis considered was primary systemic ANCA vasculitis. Although rare, ILD changes are also seen in MPO positive ANCA vasculitis. The association between interstitial lung disease (ILD) and ANCA-associated vasculitis (AAV), particularly myeloperoxidase MPO - ANCA has been described in the last 2 decades. Given the mild clubbing and rapidly progressing UIP, the alternative diagnosis could have been IPF. However, ENT symptoms and joint pains are usually not associated with IPF. Given the initial response to steroids, further immunosuppression with MMF was started. However, a few days later he was hospitalised due to severe dyspnoea and episodes of haemoptysis. The CT showed new GCO changes on the background of UIP changes and no PE. The dilemma was whether it was drug-induced acute exacerbation of interstitial pneumonitis or natural acceleration of UIP. It was unclear whether he had 2 different pathologies. Disease stratification and early identification of patients who are more prone to progress, and thus in need of more aggressive treatment, is important in the field of ILD. Key learning points There is still significant challenge in the diagnosis and management of ILD. It was unclear whether this case was IPF or MPO vasculitis. There are no specific diagnostic markers and there are no consensus clear guidelines on managing ILD. Although considerable progress has been made in understanding ILD, curing and eliminating interstitial lung disease is still a distant goal. A clearer understanding of how the cells fail to adequately repair the lung and key pathogenetic pathways are much needed and require further exploration. Current clinical trials are studying agents that reduce the fibrotic signalling within the lung, reduce pulmonary hypertension associated with interstitial lung disease, and alleviate oxidative stress. Early diagnosis, monitoring and MDT input are essential to improve overall outcomes. This case illustrates the complexity faced by clinicians in the management of ILD patients in the real-life setting and raises a number of points outside of the clinical guidelines. Conflict of interest The authors declare no conflicts of interest.

Introduction Auto-immune and auto-inflammatory disorders are believed to cause approximately 20% of cases of pyrexia of unknown origin. Rheumatological opinion is often sought when an infectious source has not been detected. Assessment of recurrent fever is challenging for fear of initiating immunosuppression in the presence of undetected infection. This challenge is even greater in patients with a previous history of auto-immune or infectious disorders. Here, we discuss the investigation and management of a challenging case of recurrent fever, ultimately diagnosed as adult-onset Still’s disease, complicated by the previous occurrence of pulmonary tuberculosis and myasthenia gravis. Case description Our 34-year-old female patient, originally from India, had lived in the UK for 8 years. Her background included previous treatment for pulmonary TB in 2011 and myasthenia gravis diagnosed in 2015 with subsequent thoracoscopic thymectomy in 2016. She was admitted to the infectious diseases unit in October 2016 with 3 weeks of recurrent fever and an itchy rash which had commenced 1-week after holidaying in Spain. Pyrexiae were quotidian, occurring nocturnally and would usually last 1 hour with associated malaise and tachycardia. The rash affected the upper arms, buttocks and face but was not consistent in appearance; initially urticarial and later described as maculopapular. Polyarthralgia of the joints of the hands was reported. Extensive infection screening including blood cultures and serology was negative. A CT-CAP revealed changes of old TB and borderline axillary lymphadenopathy. Immunology revealed a negative ANA and ENA screen along with normal levels of anti-PR3, MPO, DsDNA and CCP antibodies. Further investigations included a CRP of 213, ESR of 75 and serum ferritin of 450mcg/l (15-200). A provisional diagnosis of a periodic fever syndrome was made and the patient agreed to a trial of anti-interleukin 1 therapy (Anakinra 100mg SC OD) while awaiting genetic testing. Immediate defervescence of fever occurred with an improvement in the rash and dramatic reduction in inflammatory indices. Two months later the patient represented with malaise, tachycardia, periorbital odema, widespread rash, diarrhoea and a marked peripheral eosinophilia (5.69 x109/L). Skin biopsy demonstrated vacuolar inflammation and prominent eosinophils. A diagnosis of DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome was made and anakinra was withdrawn. However, the patient’s condition deteriorated with a rebound elevation in inflammatory markers, pyrexia and development of synovitis. Repeat serum ferritin during this period was recorded at > 40,000mcg/ml and a diagnosis of adult-onset Still’s disease was made. Discussion This case was challenging on two particular fronts. Firstly, the arrival of a confident and definitive diagnosis was difficult. On initial review and again on deterioration 2 months later, the patient’s previous history of TB, recent travel history and presence of lymphadenopathy led to significant concern of an alternative primary diagnosis. A large number of investigations for occult infection (e.g. TB recurrence) and malignancy (e.g. lymphoma) were conducted. Likewise, the absence of a history of a sore throat, the atypical skin rash, a very modest elevation in serum ferritin, and the absence of synovitis made adult-onset Still’s disease less likely. However, the rapidity and magnitude of the response to Interleukin-1 inhibition with anakinra supported our suspicion of an auto-inflammatory syndrome. The second hurdle in this case was the problematic pharmaceutical management once adult-onset Still’s disease was diagnosed. The occurrence of DRESS syndrome secondary to anakinra is not something we had previously experienced nor does it appear to have been reported in the literature before despite a relatively high incidence of anaphylaxis and localized skin reactions with anakinra. Subsequent interleukin-6 blockade with tocilizumab was partially effective in improving symptoms and clinical parameters but did lead to significant derangement in liver function tests and treatment was stopped. There was an incomplete response to TNF-α inhibition with weekly subcutaneous etanercept injections in combination with high dose oral corticosteroids. Subsequently there was a good response to the monoclonal antibody canakinumab (anti-IL-1β). Our patient remains on 10mg of oral prednisolone but has largely remained in remission for 18 months in combination with canakinumab. Remaining concerns relate to the long-term efficacy of canakinumab for this patient and the limited therapeutic options if recurrent relapses occur. Furthermore, the risk of TB re-activation remains an unavoidable risk with a high degree of clinical suspicion required. Key learning points This was a challenging case complicated by the patient’s past medical history of TB, myasthenia gravis and thymoma, in addition to the occurrence of DRESS syndrome which led to a period of diagnostic uncertainty. While the input of many specialties (i.e., respiratory, infectious diseases, haematology, and dermatology) were required and critical to the overall management of the patient, extensive and prolonged investigation can lead to significant delays in treatment. In such situations, an open discussion with the patient as to the risks and benefits of delaying treatment versus pursuing further investigation is advised. Furthermore, we have learnt from this case to appreciate that focused repetition of some investigations, in the setting of diagnostic uncertainty, can be beneficial. In this case repetition of serum ferritin levels, skin biopsy and cross-sectional CT imaging all led to important diagnostic conclusions and decisions that ultimately resulted in the correct diagnosis and successful management of this patient. Conflict of interest The authors declare no conflicts of interest.

OBJECTIVES: The aim was to examine the clinical course and dietary patterns among patients incorporating autoimmune protocol (AIP) for management of inflammatory bowel disease (IBD). METHODS: An anonymous online survey was sent through electronic newsletters and support groups utilizing AIP. The survey assessed demographics, IBD disease activity, and medication use. Participants were asked about AIP utilization and food group reintroductions. Abdominal pain (AP), stool frequency (SF), and rectal bleeding (RB) were compared at baseline (BL, prior to starting AIP), week 6 (after starting AIP), and present, for both Crohn's disease (CD) and ulcerative colitis (UC). RESULTS: There were 78 respondents. Mean age was 39.4 years, with mean IBD duration 13.2 years. 78% had prior steroid exposure. 35% currently on immunosuppressive agents. 73% perceived achieving clinical remission due to AIP. This was more common among patients not on immunosuppression (76% vs. 24% on immunosuppression, P

Ependymoma is the third commonest childhood brain tumour. Relapse is frequent, often fatal and current therapeutic strategies are inadequate. Previous ependymoma research describes an immunosuppressive environment with T-cell exhaustion, indicating a lack of response to T-cell directed immunotherapy. Understanding the immune microenvironment is therefore critical. We present a computational analysis of ependymoma, gene expression derived, immune profiles. Using 465 ependymoma samples from gene expression datasets (GSE64415, GSE50385, GSE100240) and two RNA-seq databases from UK ependymomas, we applied bulk tumour deconvolution methods (CIBERSORT and xCell) to infer immune cell populations. Additionally, we measured checkpoint blockade related mRNAs and used immunohistochemistry to investigate cell populations in ependymoma sections. CIBERSORT indicated high proportions of M2-like macrophages and smaller proportions of activated natural killer (NK) cells, T follicular helper cells, CD4+ memory T-cells and B-cells. xCell overlapped with the M2-like macrophage and CD4+ memory T-cell signatures seen in CIBERSORT. On immunohistochemistry, T and B cells were scarce, with small numbers of CD8+, CD4+ and CD20+ cells in the parenchyma but greater numbers in surrounding regions. CD68 was more highly expressed in the parenchyma. Analysis of nine checkpoint ligands and receptors demonstrated only the TIM3/GAL9 combination was reliably detectable. GAL9 is implicated in tumour interactions with T-cells and macrophages elsewhere, possibly contributing to poorer outcomes. Our study supports the presence of myeloid cells being leading contributors to the ependymoma immune microenvironment. Further work will delineate the extent of myeloid contribution to immunosuppression across molecular subtypes. Modulation of tumour immunity may contribute to better clinical outcomes.

Background Histoplasmosis is known to cause CNS infection with or without disseminated disease and immunosuppression is a risk factor. It can mimic brain tumor and present a diagnostic challenge. Methods Case report and literature review using PUBMED. Results A 64-year-old white female with myasthenia gravis on mycophenolate mofetil, history of Meniere’s Disease, presented with worsening ataxia and left-sided facial weakness for 4 days. MRI revealed multiple enhancing lesions within the brainstem and supratentorial parenchyma (Figure 1), consistent with metastases but either too small or inaccessible for biopsy. Work up for primary cancer with CT thorax, abdomen-pelvis, transvaginal US, mammogram, bone scan, and CSF cytology were negative. The CSF BioFire PCR and culture were negative. Prednisone taper was started for brain vasogenic edema. Patient presented again two months later with worsening lethargy, vertigo, and recurrent falls. At that time the brain lesions showed continued enlargement on repeat imaging, and stereotactic biopsy was performed. Histopathology showed non-necrotizing granulomas, no evidence of malignancy, but after 12 days a mold was isolated on culture prompting Infectious Diseases consultation. Initial morphologic features were non-diagnostic and empiric voriconazole was initiated. Fungal culture evolved Histoplasma capsulatum and voriconazole was switched to liposomal amphotericin B at 5 mg/kg intravenously every 24 hours. Histoplasma serology was positive at low titer, urine histoplasma antigen was negative. An 8 weeks course of Amphotericin, followed by lifelong suppression with fluconazole, was planned. Figure 1 Conclusion The diagnosis of our patient’s brain lesions was challenging as biopsy was not an option initially. An anchoring bias likely existed as the investigations had focused on malignancy, while a more robust evaluation for opportunistic endemic fungi, such as Histoplasma, took place at a later stage. Brain lesions in the immunosuppressed patient can masquerade as malignancy. To ensure timely diagnosis, a multimodal investigational approach should be applied early to include imaging and laboratory evaluation for endemic opportunistic pathogens, as well as biopsy when possible. Disclosures All Authors: No reported disclosures

Background Immunocompromised (IC) populations are at increased risk of developing herpes zoster (HZ) due to disease- and/or therapy-induced immunosuppression. The adjuvanted recombinant zoster vaccine (RZV) has demonstrated 68.2% efficacy in preventing HZ in autologous hematopoietic stem cell transplant (HSCT) recipients and 87.2% efficacy in a post-hoc analysis in hematologic malignancy (HM) patients ≥ 18 years of age (YOA). Here we present the immunogenicity of RZV in representative IC populations. Methods Our analysis includes five phase I/II/III clinical trials conducted worldwide between 2010–2017 (Table 1) in IC populations (autologous HSCT, human immunodeficiency virus [HIV]-infected, HM, solid tumor [ST] on chemotherapy and renal transplant [RT] patients) ≥ 18 YOA. Anti-glycoprotein E (gE) antibody geometric mean concentrations (GMCs) and gE-specific CD4 T cell frequencies were descriptively evaluated by age group (18–49 YOA and ≥ 50 YOA) and overall at 1 month (M) and 12M post-last RZV dose. Table 1. Clinical studies with immunocompromised populations included in our analysis Results The according-to-protocol cohorts for immunogenicity from the included trials are presented in Table 1. At 1M post-last RZV dose, anti-gE GMCs and median CD4 T-cell frequencies increased in all IC populations compared to pre-vaccination and persisted above baseline up to 12M post-last RZV dose (Figures 1 and 2). No meaningful differences were seen between age groups in terms of humoral (except a slight trend for stronger responses in the 18–49 YOA RT and HM patients compared to their corresponding ≥ 50 YOA group) and gE-specific CD4 T-cell responses in any of the IC populations. Figure 1. Humoral immune responses to RZV in immunocompromised populations (adapted ATP cohort for humoral immunogenicity) Figure 2. Cell-mediated immune responses to RZV in immunocompromised populations (adapted ATP cohort for cell-mediated immunogenicity) Conclusion RZV induced robust and persistent humoral and cell-mediated immune (CMI) responses that lasted up to at least 12M post-last vaccination in all evaluated IC populations. Humoral responses in the IC populations were robust although not as strong as in the non-IC adults ≥ 50 YOA. CMI responses were mostly similar across IC populations and adults ≥ 50 YOA, with a potent response occurring even in ST patients undergoing chemotherapy. This data shows that RZV is immunogenic even in severely IC adults. Funding: GlaxoSmithKline Biologicals SA Acknowledgment: M Maior/S Hulsmans (Modis c/o GSK) provided writing/editorial support Disclosures Alemnew F. Dagnew, MD, MSc, GSK group of companies (Employee, Shareholder) Peter Vink, MD, GSK group of companies (Employee, Shareholder) Mamadou Drame, MSc, GSK group of companies (Employee) David Willer, PhD, GSK group of companies (Employee, Shareholder) Bruno Salaun, PhD, GSK group of companies (Employee) Anne Schuind, MD, GSK (Employee, Other Financial or Material Support, own GSK stock options or restricted shares as part of renumeration)

BACKGROUND D2C7 immunotoxin (D2C7-IT) is a dual-specific recombinant immunotoxin comprising an EGFR-wt and mutant-specific (EGFRvIII) monoclonal antibody fragment and a genetically engineered form of the pseudomonas exotoxin. When injected directly into the tumor mass by convection enhanced delivery (CED), in addition to direct tumor cell killing, immunotoxins induce secondary immune responses by the activation of CD4+ and CD8+ T-cells. We completed a phase 1 dose escalation study of D2C7-IT injected by CED into recurrent WHO grade III-IV MG and identified the phase 2 dose (6,920 ng/mL). Three patients remain in partial response more than 58, 38, and 32 months after a single D2C7-IT intratumoral infusion. As optimal induction of anti-tumor immune responses by immunotoxins is impeded by potent MG-mediated immunosuppression, we are assessing the toxicity of the combination of D2C7-IT with atezolizumab in patients with recurrent WHO grade IV MG. METHODS Eligibility includes adult patients with recurrence of a solitary supratentorial WHO grade IV MG; ≥4 weeks after chemotherapy, bevacizumab or study drug; adequate organ function; and KPS >70%. Patient receives an intratumoral infusion of D2C7-IT and initiates two weeks later atezolizumab at 1200mg, followed by atezolizumab every 3 weeks for up to 2 years. Two cohorts of 3 patients are initially accrued to assess the toxicity of the combination. Assuming accrual continues after the initial two cohorts of 3 patients, an additional 12 patients will be accrued to the study. RESULT The first enrolled patient experienced a grade 3 DLT (grade III ALT elevation) after the first infusion of atezolizumab, but showed a more extensive immunotherapeutic effect by imaging than observed with patients on the D2C7-IT monotherapy trial. Enrollment is ongoing. CONCLUSION D2C7-IT monotherapy has shown prolonged survival and disease control in some patients. We are now evaluating the combination of D2C7-IT with checkpoint inhibition.